Nonhuman primate (NHP) models will expedite therapeutics and vaccines for COVID-19 into clinical trials. We compared acute SARS-CoV-2 infection in young and old rhesus macaques and baboons and old marmosets. Macaques had clinical signs of viral infection, mild-to-moderate pneumonitis and extra-pulmonary pathologies; both age groups recovered in two weeks. Baboons had prolonged viral RNA shedding and substantially more lung inflammation compared with macaques. Inflammation in bronchoalveolar lavage (BAL) was increased in old versus young baboons. Using techniques like CT imaging, immunophenotyping, alveolar/peripheral cytokine responses and immunohistochemical analyses, we delineated cellular immune responses to SARS-CoV-2 infection in macaque and baboon lungs, including innate and adaptive immune cells and a prominent Type I-interferon response. Macaques developed T cell memory phenotype/responses and bystander cytokine production. Old macaques had lower titres of SARS-CoV-2-specific IgG antibody levels compared with young. Acute respiratory distress in macaques and baboons recapitulates the progression of COVID-19 in humans, making them suitable as models to test vaccines and therapies.

Large studies on bedaquiline used to treat multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) are lacking. This study aimed to evaluate the safety and effectiveness of bedaquiline-containing regimens in a large, retrospective, observational study conducted in 25 centres and 15 countries in five continents.428 culture-confirmed MDR-TB cases were analysed (61.5% male; 22.1% HIV-positive, 45.6% XDR-TB). MDR-TB cases were admitted to hospital for a median (interquartile range (IQR)) 179 (92-280) days and exposed to bedaquiline for 168 (86-180) days. Treatment regimens included, among others, linezolid, moxifloxacin, clofazimine and carbapenems (82.0%, 58.4%, 52.6% and 15.3% of cases, respectively).Sputum smear and culture conversion rates in MDR-TB cases were 63.6% and 30.1%, respectively at 30 days, 81.1% and 56.7%, respectively at 60 days; 85.5% and 80.5%, respectively at 90 days and 88.7% and 91.2%, respectively at the end of treatment. The median (IQR) time to smear and culture conversion was 34 (30-60) days and 60 (33-90) days. Out of 247 culture-confirmed MDR-TB cases completing treatment, 71.3% achieved success (62.4% cured; 8.9% completed treatment), 13.4% died, 7.3% defaulted and 7.7% failed. Bedaquiline was interrupted due to adverse events in 5.8% of cases. A single case died, having electrocardiographic abnormalities that were probably non-bedaquiline related.Bedaquiline-containing regimens achieved high conversion and success rates under different nonexperimental conditions.

While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4 + T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4 + T cells were poorly restored specifically in the lung interstitium, despite their significant restoration in the alveolar compartment of the lung as well as in the periphery. IDO1 induction in myeloid cells in the inducible bronchus-associated lymphoid tissue (iBALT) likely contributed to dysregulated T cell homing and impaired lung immunity. Thus, although ART was indispensable for controlling viral replication, restoring CD4 + T cells, and preventing opportunistic infection, it appeared inadequate in reversing the clinical signs of TB reactivation during the relatively short duration of ART administered in this study. This finding warrants the modeling of concurrent treatment of TB and HIV to potentially reduce the risk of reactivation of TB due to HIV to inform treatment strategies in patients with M. tuberculosis/HIV coinfection.

SummaryThere are no known cures or vaccines for COVID-19, the defining pandemic of this era. Animal models are essential to fast track new interventions and nonhuman primate (NHP) models of other infectious diseases have proven extremely valuable. Here we compare SARS-CoV-2 infection in three species of experimentally infected NHPs (rhesus macaques, baboons, and marmosets). During the first 3 days, macaques developed clinical signatures of viral infection and systemic inflammation, coupled with early evidence of viral replication and mild-to-moderate interstitial and alveolar pneumonitis, as well as extra-pulmonary pathologies. Cone-beam CT scans showed evidence of moderate pneumonia, which progressed over 3 days. Longitudinal studies showed that while both young and old macaques developed early signs of COVID-19, both groups recovered within a two-week period. Recovery was characterized by low-levels of viral persistence in the lung, suggesting mechanisms by which individuals with compromised immune systems may be susceptible to prolonged and progressive COVID-19. The lung compartment contained a complex early inflammatory milieu with an influx of innate and adaptive immune cells, particularly interstitial macrophages, neutrophils and plasmacytoid dendritic cells, and a prominent Type I-interferon response. While macaques developed moderate disease, baboons exhibited prolonged shedding of virus and extensive pathology following infection; and marmosets demonstrated a milder form of infection. These results showcase in critical detail, the robust early cellular immune responses to SARS-CoV-2 infection, which are not sterilizing and likely impact development of antibody responses. Thus, various NHP genera recapitulate heterogeneous progression of COVID-19. Rhesus macaques and baboons develop different, quantifiable disease attributes making them immediately available essential models to test new vaccines and therapies.

Antigen-specific T cell responses are critical for immune control of M. tuberculosis infection. In response to M. tuberculosis infection, the majority of infected people mount robust CD4 + T cell responses involving Th1 cytokines, such as IFN-γ and TNF-α, which are important for activating macrophages and curtailing M. tuberculosis replication in the lung (6, 7). In addition, IL-17 and Th17 responses have emerged as important for protective immunity against TB (8,9). Animal studies have shown a role for IL-17 in induction of chemokines, recruitment of CD4 + T cells to the site of infection, formation of granulomas, and protection during M. tuberculosis infection and Bacille Calmette-Guérin (BCG) vaccination (10)(11)(12)(13)(14)(15)(16)(17)(18). The role of IL-17 and Th17 responses in human TB is less clear and has been mainly studied by comparing individuals with active TB and healthy controls. Reports from humans vary widely, with studies showing no difference in the levels of IL-17 between the groups (19), while others have seen low levels of IL-17 in patients with TB compared with healthy controls (20,21). Human genetic mutations and polymorphisms in IL-17 have been associated with TB susceptibility (12,22), whereas other studies have shown the association of Th17/IL-17 responses with TB pathogenesis and disease progression (23)(24)(25)(26). Overall, how IL-17, and in particular, M. tuberculosis antigen-specific Th17 cells, function to control M. tuberculosis infection during asymptomatic LTBI in humans remains poorly understood. We have limited knowledge of the onset and maintenance of M. tuberculosis antigen-specific Th1 and Th17 cell responses in the blood and lung compartments during LTBI and of the phenotypes and functions associated with the LTBI state. This is in part because small-animal models do not reproduce key aspects of human LTBI. Moreover, accurately documenting M. tuberculosis exposure, initial infection, and early events following infection in humans is almost impossible. Thus, studies of M. tuberculosis antigen-specific T cells in humans have been largely confined to cross-sectional characterization of peripheral responses in the blood (27)(28)(29)(30)(31). While some studies have examined responses in bronchoalveolar lavage (BAL) (32-34), longitudinal studies in humans comparing M. tuberculosis antigen-specific T cell responses in blood and lung compartments have been lacking. Thus, detailed characterization of the nature and kinetics of M. tuberculosis antigen-specific T cells associated with human-like asymptomatic LTBI is important for identifying correlates of immune control and protection.Nonhuman primate (NHP) macaque models of M. tuberculosis infection recapitulate multiple features of human M. tuberculosis infection, including clinically asymptomatic infection and symptomatic active TB disease (35-42), and are attractive for studying immune parameters associated with control of M. tuberculosis infection in peripheral blood and lung compartments. We have previously established a mode...

We report the experiences of 5 patients taking bedaquiline with delamanid in combination: 1 patient was cured; 3 culture converted, with 2 continuing and 1 changing therapy; and 1 died from respiratory insufficiency. For 2 patients, QT-interval prolongation but no arrhythmias occurred. Use of this therapy is justified for patients with limited options.

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